Deletion of protein kinase C θ attenuates hepatic ischemia/reperfusion injury and further elucidates its mechanism in pathophysiology.

Objectives: Hepatic ischemia-reperfusion (HIR) is a severe process in pathophysiology that occurs clinically in hepatectomy, and hepatic transplantations. The present study aimed to investigate the effect of PKC θ deletion against HIR injury and elucidate its mechanism in pathophysiology. Materials and Methods: HIR injury was induced in wild-type and PKC θ deletion mice treated with or without heme. The ALT and AST levels were determined to evaluate liver function. HIR injury was observed via histological examination. Oxidative stress and inflammatory response markers, and their signaling pathways were detected. Results: The study found that PKC θ knockout decreased serum AST and ALT levels when compared to the WT mice. Furthermore, heme treatment significantly reduced the ALT and AST levels of the PKC θ deletion mice compared with the untreated PKC θ deletion mice. PKC θ deletion markedly elevated superoxide dismutase activity in the liver tissue, reduced malondialdehyde content in the tissue, and the serum TNF-α and IL-6 levels compared with the WT mice. Heme treatment was observed to elevate the activity of SOD and reduced MDA content and serum of TNF-α and IL 6 in the PKC θ deletion animals. Meanwhile, heme treatment increased HO-1 and Nrf 2 protein expression, and reduced the levels of TLR4, phosphorylated NF-κB, and IKB-α. Conclusion: These findings suggested that PKC θ deletion ameliorates HIR, and heme treatment further improves HIR, which is related to regulation of PKC θ deletion on Nrf 2/HO-1 and TLR4/NF-κB/IKB α pathway.

Convective Water Vapour Energy Ablation (Rezum®) versus Prostatic Urethral Lift (Urolift®); A 2-Year Prospective Study.

Introduction To compare the clinical outcomes and complication rates of Convective Water Vapour Energy Ablation (Rezum®) and Prostatic Urethral Lift (Urolift®). To identify predictive factors for treatment failures in both treatments. Materials & Methods Prospective clinico-epidemiological data of patients who underwent Urolift® or Rezum® in a single institution for Benign Prostatic Hyperplasia (BPH) was collected. The choice of intervention depended on the preference of the patients after patient-centric discussions. Results From October 2019 to October 2022, 86 patients underwent Rezum® and 62 patients underwent Urolift®. Rezum® involved a longer indwelling catheter duration (12.38±5.548 versus 1.39±3.010 days, p<0.001) compared to Urolift®. Rezum® was associated with more complications compared to Urolift® (36 (41.9%) versus 10 (16.1%) cases, p<0.001). Rezum® had more cases of hematuria (17 (19.8%) versus 4 (6.5%) cases (p=0.022)) and urinary tract infections (27 (31.4%) versus 3 (4.8%) cases, p<0.001)), compared to Urolift®. There were no significant differences in Clavien-Dindo Grade 3-5 complications between the interventions. Urolift® was associated with higher re-operation rates (5 (8.1%) versus 0 (0%) cases, p=0.010) compared Rezum®. Rezum® had higher anti-cholinergic usage rates compared to Urolift® post-operation (22 (25.6%) versus 8 (12.9%) cases, p=0.024). Both interventions showed improvement in International Prostate Symptom Score (IPSS), Quality of Life score, and peak velocity flow over the 2 years with no significant difference between the two. Based on receiver operating characteristic curve, pre-operation IPSS ≥ 16 had 95.7% sensitivity and 38.4% specificity to predict the probability of treatment failures after the interventions. Conclusions There was no difference in clinical outcomes of patients who underwent Rezum® and Urolift®. However, patients who had undergone Rezum® faced more minor complications and more required anti-cholinergic medications. Lastly, physicians should note that patients with IPSS≥16 would unlikely benefit from either intervention.

Glycoengineering with neuraminic acid analogs to label lipooligosaccharides and detect native sialyltransferase activity in gram-negative bacteria.

Lipooligosaccharides are the most abundant cell surface glycoconjugates on the outer membrane of Gram-negative bacteria. They play important roles in host-microbe interactions. Certain Gram-negative pathogenic bacteria cap their lipooligosaccharides with the sialic acid, N-acetylneuraminic acid (Neu5Ac), to mimic host glycans that among others protects these bacteria from recognition by the hosts immune system. This process of molecular mimicry is not fully understood and remains under investigated. To explore the functional role of sialic acid-capped lipooligosaccharides at the molecular level, it is important to have tools readily available for the detection and manipulation of both Neu5Ac on glycoconjugates and the involved sialyltransferases, preferably in live bacteria. We and others have shown that the native sialyltransferases of some Gram-negative bacteria can incorporate extracellular unnatural sialic acid nucleotides onto their lipooligosaccharides. We here report on the expanded use of native bacterial sialyltransferases to incorporate neuraminic acids analogs with a reporter group into the lipooligosaccharides of a variety of Gram-negative bacteria. We show that this approach offers a quick strategy to screen bacteria for the expression of functional sialyltransferases and the ability to use exogenous CMP-Neu5Ac to decorate their glycoconjugates. For selected bacteria we also show this strategy complements two other glycoengineering techniques, Metabolic Oligosaccharide Engineering and Selective Exo-Enzymatic Labeling, and that together they provide tools to modify, label, detect and visualize sialylation of bacterial lipooligosaccharides.

Evaluating the embryotoxicity of benzophenone-based photoinitiators in stem cells and zebrafish embryos.

Benzophenones (BPs) are widely used as photoinitiators (PIs) or printing inks in food packaging, which may migrate into foods. However, the toxicity information of some BP analogues, such as 4,4'-bis(diethylamino)-benzophenone (DEAB), 4-phenylbenzophenone (4-PBP), 4 (hydroxymethyl)benzophenone (4-HMBP), those are used as PIs is lacking. Developmental toxicity is a health concern associated with PIs exposure. Recently, alternative non-in vivo methods have been proposed to evaluate the concerned chemicals or better understand the modes of action of certain toxicological endpoints. In this study, using in silico methods, we predicted that BP, DEAB, 4-PBP and 4-HMBP might exhibit developmental toxicity. However, we found that only DEAB is strong embryotoxic and disturbs the early differentiation of mouse embryonic stem cells into three germ layers and cardiomyocytes. DEAB treatment also prevented cardiomyocyte differentiation in human induced pluripotent stem cells (hiPSCs) on day 10. However, BP, 4-PBP and 4-HMBP had no similar effects on cardiomyocyte differentiation on day 10. Transcriptomic analysis revealed that treatment with DEAB significantly decreased the mRNA levels of differentiation-related transcription factors SOX17 and FOXA1, in hiPSCs on day 4. Furthermore, DEAB treatment caused tail malformations and yolk sac edema in zebrafish embryos. To conclude, DEAB may be embryotoxic because it disturbs the early differentiation of stem cells. Further studies are warranted to better understand the health effects of DEAB exposure.

The causal effect of gut microbiota on hepatic encephalopathy: a mendelian randomization analysis.

BACKGROUND: There is growing evidence for a relationship between gut microbiota and hepatic encephalopathy (HE). However, the causal nature of the relationship between gut microbiota and HE has not been thoroughly investigated. METHOD: This study utilized the large-scale genome-wide association studies (GWAS) summary statistics to evaluate the causal association between gut microbiota and HE risk. Specifically, two-sample Mendelian randomization (MR) approach was used to identify the causal microbial taxa for HE. The inverse variance weighted (IVW) method was used as the primary MR analysis. Sensitive analyses were performed to validate the robustness of the results. RESULTS: The IVW method revealed that the genus Bifidobacterium (OR = 0.363, 95% CI: 0.139-0.943, P = 0.037), the family Bifidobacteriaceae (OR = 0.359, 95% CI: 0.133-0.950, P = 0.039), and the order Bifidobacteriales (OR = 0.359, 95% CI: 0.133-0.950, P = 0.039) were negatively associated with HE. However, no causal relationship was observed among them after the Bonferroni correction test. Neither heterogeneity nor horizontal pleiotropy was found in the sensitivity analysis. CONCLUSION: Our MR study demonstrated a potential causal association between Bifidobacterium, Bifidobacteriaceae, and Bifidobacteriales and HE. This finding may provide new therapeutic targets for patients at risk of HE in the future.

In Situ Fe/Co/B Codoped MoS2 Ultrathin Nanosheets Enable Efficient Electrocatalytic Nitrogen Reduction.

The development of sustainable and effective electrochemical nitrogen fixation catalysts is crucial for the mitigation of the terrible energy consumption resulting from the Haber-Bosch process. Molybdenum disulfide (MoS2) exhibits promise toward nitrogen reduction reaction (NRR) on account of its similar structure to natural nitrogenases MoFe-co but still undergoes serious challenges with unsatisfactory catalytic performance resulted from limited active sites, conductivity, and selectivity. In this work, Fe/Co/B codoped MoS2 ultrathin nanosheets are synthesized and verified as excellent NRR catalysts with high activity, selectivity, and durability. The FeCoB-MoS2 demonstrates a high ammonia yield of 36.99 µg h-1 mgcat-1 at -0.15 V vs RHE and Faraday efficiency (FE) of 30.65% at -0.10 V vs RHE in 0.1 M HCl. The experimental results and the density functional theory (DFT) calculations emphasize that codoping of Fe, Co, and B into MoS2 synergistically enhances its conductivity and optimizes the electronic structure of the catalyst, which significantly improves the electrocatalytic ammonia synthesis performance. This work broadens the potential and enlightens the strategy for designing efficient electrocatalysts in the NRR field.

Red nucleus mGluR2 but not mGluR3 mediates inhibitory effect in the development of SNI-induced neuropathological pain by suppressing the expressions of TNF-α and IL-1ß.

Our previous study has verified that activation of group Ⅰ metabotropic glutamate receptors (mGluRⅠ) in the red nucleus (RN) facilitate the development of neuropathological pain. Here, we further discussed the functions and possible molecular mechanisms of red nucleus mGluR Ⅱ (mGluR2 and mGluR3) in the development of neuropathological pain induced by spared nerve injury (SNI). Our results showed that mGluR2 and mGluR3 both were constitutively expressed in the RN of normal rats. At 2 weeks post-SNI, the protein expression of mGluR2 rather than mGluR3 was significantly reduced in the RN contralateral to the nerve lesion. Injection of mGluR2/3 agonist LY379268 into the RN contralateral to the nerve injury at 2 weeks post-SNI significantly attenuated SNI-induced neuropathological pain, this effect was reversed by mGluR2/3 antagonist EGLU instead of selective mGluR3 antagonist ß-NAAG. Intrarubral injection of LY379268 did not alter the PWT of contralateral hindpaw in normal rats, while intrarubral injection of EGLU rather than ß-NAAG provoked a significant mechanical allodynia. Further studies indicated that the expressions of nociceptive factors TNF-α and IL-1ß in the RN were enhanced at 2 weeks post-SNI. Intrarubral injection of LY379268 at 2 weeks post-SNI significantly suppressed the overexpressions of TNF-α and IL-1ß, these effects were reversed by EGLU instead of ß-NAAG. Intrarubral injection of LY379268 did not influence the protein expressions of TNF-α and IL-1ß in normal rats, while intrarubral injection of EGLU rather than ß-NAAG significantly boosted the expressions of TNF-α and IL-1ß. These findings suggest that red nucleus mGluR2 but not mGluR3 mediates inhibitory effect in the development of SNI-induced neuropathological pain by suppressing the expressions of TNF-α and IL-1ß. mGluR Ⅱ may be potential targets for drug development and clinical treatment of neuropathological pain.

BsuMI regulates DNA transformation in Bacillus subtilis besides the defense system and the constructed strain with BsuMI-absence is applicable as a universal transformation platform for wild-type Bacillus.

BACKGROUND: To effectively introduce plasmids into Bacillus species and conduct genetic manipulations in Bacillus chassis strains, it is essential to optimize transformation methods. These methods aim to extend the period of competence and enhance the permeability of the cell membrane to facilitate the entry of exogenous DNA. Although various strategies have been explored, few studies have delved into identifying metabolites and pathways associated with enhanced competence. Additionally, derivative Bacillus strains with non-functional restriction-modification systems have demonstrated superior efficiency in transforming exogenous DNA, lacking more explorations in the regulation conducted by the restriction-modification system to transformation process. RESULTS: Transcriptomic comparisons were performed to discover the competence forming mechanism and the regulation pathway conducted by the BsuMI methylation modification group in Bacillus. subtilis 168 under the Spizizen transformation condition, which were speculated to be the preferential selection of carbon sources by the cells and the preference for specific metabolic pathway when utilizing the carbon source. The cells were found to utilize the glycolysis pathway to exploit environmental glucose while reducing the demand for other phosphorylated precursors in this pathway. The weakening of these ATP-substrate competitive metabolic pathways allowed more ATP substrates to be distributed into the auto-phosphorylation of the signal transduction factor ComP during competence formation, thereby increasing the expression level of the key regulatory protein ComK. The expression of ComK upregulated the expression of the negative regulator SacX of starch and sucrose in host cells, reinforcing the preference for glucose as the primary carbon source. The methylation modification group of the primary protein BsuMI in the restriction-modification system was associated with the functional modification of key enzymes in the oxidative phosphorylation pathway. The absence of the BsuMI methylation modification group resulted in a decrease in the expression of subunits of cytochrome oxidase, leading to a weakening of the oxidative phosphorylation pathway, which promoted the glycolytic rate of cells and subsequently improved the distribution of ATP molecules into competence formation. A genetic transformation platform for wild-type Bacillus strains was successfully established based on the constructed strain B. subtilis 168-R-M- without its native restriction-modification system. With this platform, high plasmids transformation efficiencies were achieved with a remarkable 63-fold improvement compared to the control group and an increased universality in Bacillus species was also obtained. CONCLUSIONS: The enhanced competence formation mechanism and the regulation pathway conducted by the functional protein BsuMI of the restriction-modification system were concluded, providing a reference for further investigation. An effective transformation platform was established to overcome the obstacles in DNA transformations in wild-type Bacillus strains.

Resection of polyps involving the appendiceal orifice by combined endo-laparoscopic surgery: Two case reports.

BACKGROUND: The management of polyps involving the appendiceal orifice (AO) presents notable challenges. Endoscopic resection is frequently hindered by operational complexities, a heightened risk of incomplete removal, and an elevated risk of procedural complications, including appendicitis. Conversely, surgical resection may entail unnecessary excision of intestinal segments, leading to potential morbidity. CASE SUMMARY: Here, we reported two patients who presented with polyps deeply situated within the AO, with indistinct boundaries making it challenging to ensure completeness using traditional endoscopic resection. To overcome these challenges, we employed combined endo-laparoscopic surgery (CELS), achieving curative resection without postoperative complications. CONCLUSION: The application of CELS in managing polyps involving the AO is emerging as a safe and effective treatment modality.

Influential factors associated with core competencies of diabetes specialist nurses and correlation with self-directed learning ability: A cross-sectional study.

AIMS AND OBJECTIVES: This study aimed to investigate the current status of the core competencies and self-directed learning ability of diabetes specialist nurses and to explore the relationship between these core competencies and their self-directed learning ability. DESIGN: A cross-sectional survey design was used. METHODS: This cross-sectional study was conducted via a web-based questionnaire platform in China from January 14 to April 24, 2023. The survey included a general information questionnaire, a diabetes specialist nurses' core competencies self-assessment scale, and a nursing staff's self-directed learning ability evaluation scale. The data was collected online. Descriptive, correlation and multiple linear regression analyses were conducted using SPSS 26.0 software. RESULTS: 118 diabetes specialist nurses from 11 cities participated in this study. A positive correlation was observed between the core competencies of diabetes specialist nurses and their self-directed learning ability. The characteristics affecting the core competencies of diabetes specialist nurses included age, participation in external learning and communication and self-directed learning. CONCLUSIONS: The training of diabetes specialist nurses can focus on core competencies, and the ability to self-direct learning can be used as an entry point to customize feasible theoretical and practical courses. The training system can further improve diabetes specialist nurses' core competencies and self-directed learning abilities. RELEVANCE TO CLINICAL PRACTICE: A reference can be established that nursing managers and nursing educators can use to develop training programs for specialist nurses by validating the link between their core competencies and self-directed learning skills. PATIENT OR PUBLIC CONTRIBUTION: Participants were involved solely in the data collection process. No participant contributions were required for the study's design, outcome measurement or implementation.

Red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain through stimulating the expressions of TNF-α and IL-1ß.

Our previous study has identified that glutamate in the red nucleus (RN) facilitates the development of neuropathic pain through metabotropic glutamate receptors (mGluR). Here, we further explored the actions and possible molecular mechanisms of red nucleus mGluR Ⅰ (mGluR1 and mGluR5) in the development of neuropathic pain induced by spared nerve injury (SNI). Our data indicated that both mGluR1 and mGluR5 were constitutively expressed in the RN of normal rats. Two weeks after SNI, the expressions of mGluR1 and mGluR5 were significantly boosted in the RN contralateral to the nerve injury. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN contralateral to the nerve injury at 2 weeks post-SNI significantly ameliorated SNI-induced neuropathic pain. However, unilateral administration of mGluRⅠ agonist DHPG to the RN of normal rats provoked a significant mechanical allodynia, this effect could be blocked by LY367385 or MTEP. Further studies indicated that the expressions of TNF-α and IL-1ß in the RN were also elevated at 2 weeks post-SNI. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN at 2 weeks post-SNI significantly inhibited the elevations of TNF-α and IL-1ß. However, administration of mGluR Ⅰ agonist DHPG to the RN of normal rats significantly enhanced the expressions of TNF-α and IL-1ß, these effects were blocked by LY367385 or MTEP. These results suggest that activation of red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain by stimulating the expressions of TNF-α and IL-1ß. mGluR Ⅰ maybe potential targets for drug development and clinical treatment of neuropathic pain.

Singapore tuberculosis (TB) clinical management guidelines 2024: A modified Delphi adaptation of international guidelines for drug-susceptible TB infection and pulmonary disease.

Introduction: Tuberculosis (TB) remains endemic in Singapore. Singapore's clinical practice guidelines for the management of tuberculosis were first published in 2016. Since then, there have been major new advances in the clinical management of TB, ranging from diagnostics to new drugs and treatment regimens. The National TB Programme convened a multidisciplinary panel to update guidelines for the clinical management of drug-susceptible TB infection and disease in Singapore, contextualising current evidence for local practice. Method: Following the ADAPTE framework, the panel systematically reviewed, scored and synthesised English-language national and international TB clinical guidelines published from 2016, adapting recommendations for a prioritised list of clinical decisions. For questions related to more recent advances, an additional primary literature review was conducted via a targeted search approach. A 2-round modified Delphi process was implemented to achieve consensus for each recommendation, with a final round of edits after consultation with external stakeholders. Results: Recommendations for 25 clinical questions spanning screening, diagnosis, selection of drug regimen, monitoring and follow-up of TB infection and disease were formulated. The availability of results from recent clinical trials led to the inclusion of shorter treatment regimens for TB infection and disease, as well as consensus positions on the role of newer technologies, such as computer-aided detection-artificial intelligence products for radiological screening of TB disease, next-generation sequencing for drug-susceptibility testing, and video observation of treatment. Conclusion: The panel updated recommendations on the management of drug-susceptible TB infection and disease in Singapore.

Transcriptome sequencing of the endangered land snail Karaftohelix adamsi from the Island Ulleung: De novo assembly, annotation, valuation of fitness genes and SSR markers.

BACKGROUND: The Bradybaenidae snail Karaftohelix adamsi is endemic to Korea, with the species tracked from Island Ulleung in North Gyeongsang Province of South Korea. K. adamsi has been classified under the Endangered Wildlife Class II species of Korea and poses a severe risk of extinction following habitat disturbances. With no available information at the DNA (genome) or mRNA (transcriptome) level for the species, conservation by utilizing informed molecular resources seems difficult. OBJECTIVE: In this study, we used the Illumina short-read sequencing and Trinity de novo assembly to draft the reference transcriptome of K. adamsi. RESULTS: After assembly, 13,753 unigenes were obtained of which 10,511 were annotated to public databases (a maximum of 10,165 unigenes found homologs in PANM DB). A total of 6,351, 3,535, 358, and 3,407 unigenes were ascribed to the functional categories under KOG, GO, KEGG, and IPS, respectively. The transcripts such as the HSP 70, aquaporin, TLR, and MAPK, among others, were screened as putative functional resources for adaptation. DNA transposons were found to be thickly populated in comparison to retrotransposons in the assembled unigenes. Further, 2,164 SSRs were screened with the promiscuous presence of dinucleotide repeats such as AC/GT and AG/CT. CONCLUSION: The transcriptome-guided discovery of molecular resources in K. adamsi will not only serve as a basis for functional genomics studies but also provide sustainable tools to be utilized for the protection of the species in the wild. Moreover, the development of polymorphic SSRs is valuable for the identification of species from newer habitats and cross-species genotyping.

Clinical characteristics and risk factors of post-operative intestinal flora disorder following laparoscopic colonic surgery: A propensity-score-matching analysis.

BACKGROUND: Intestinal flora disorder (IFD) poses a significant challenge after laparoscopic colonic surgery, and no standard criteria exists for its diagnosis and treatment. AIM: To analyze the clinical features and risk factors of IFD. METHODS: Patients with colon cancer receiving laparoscopic surgery were included using propensity-score-matching (PSM) methods. Based on the occurrence of IFD, patients were categorized into IFD and non-IFD groups. The clinical characteristics and treatment approaches for patients with IFD were analyzed. Multivariate regression analysis was performed to identify the risk factors of IFD. RESULTS: The IFD incidence after laparoscopic surgery was 9.0% (97 of 1073 patients). After PSM, 97 and 194 patients were identified in the IFD and non-IFD groups, respectively. The most common symptoms of IFD were diarrhea and abdominal, typically occurring on post-operative days 3 and 4. All patients were managed conservatively, including modulation of the intestinal flora (90.7%), oral/intravenous application of vancomycin (74.2%), and insertion of a gastric/ileus tube for decompression (23.7%). Multivariate regression analysis identified that pre-operative intestinal obstruction [odds ratio (OR) = 2.79, 95%CI: 1.04-7.47, P = 0.041] and post-operative antibiotics (OR = 8.57, 95%CI: 3.31-23.49, P < 0.001) were independent risk factors for IFD, whereas pre-operative parenteral nutrition (OR = 0.12, 95%CI: 0.06-0.26, P < 0.001) emerged as a protective factor. CONCLUSION: A stepwise approach of probiotics, vancomycin, and decompression could be an alternative treatment for IFD. Special attention is warranted post-operatively for patients with pre-operative obstruction or early use of antibiotics.

Interfacial Electronic Interactions Between Ultrathin NiFe-MOF Nanosheets and Ir Nanoparticles Heterojunctions Leading to Efficient Overall Water Splitting.

Creating specific noble metal/metal-organic framework (MOF) heterojunction nanostructures represents an effective strategy to promote water electrolysis but remains rather challenging. Herein, a heterojunction electrocatalyst is developed by growing Ir nanoparticles on ultrathin NiFe-MOF nanosheets supported by nickel foam (NF) via a readily accessible solvothermal approach and subsequent redox strategy. Because of the electronic interactions between Ir nanoparticles and NiFe-MOF nanosheets, the optimized Ir@NiFe-MOF/NF catalyst exhibits exceptional bifunctional performance for the hydrogen evolution reaction (HER) (η10 = 15 mV, η denotes the overpotential) and oxygen evolution reaction (OER) (η10 = 213 mV) in 1.0 m KOH solution, superior to commercial and recently reported electrocatalysts. Density functional theory calculations are used to further investigate the electronic interactions between Ir nanoparticles and NiFe-MOF nanosheets, shedding light on the mechanisms behind the enhanced HER and OER performance. This work details a promising approach for the design and development of efficient electrocatalysts for overall water splitting.

Sinapic acid modulates oxidative stress and metabolic disturbances to attenuate ovarian fibrosis in letrozole-induced polycystic ovary syndrome SD rats.

Sinapic acid (SA) is renowned for its many pharmacological activities as a polyphenolic compound. The cause of polycystic ovary syndrome (PCOS), a commonly encountered array of metabolic and hormonal abnormalities in females, has yet to be determined. The present experiment was performed to evaluate the antifibrotic properties of SA in rats with letrozole-induced PCOS-related ovarian fibrosis. SA treatment successfully mitigated the changes induced by letrozole in body weight (BW) (p < .01) and relative ovary weight (p < .05). Histological observation revealed that SA reduced the number of atretic and cystic follicles (AFs) and (CFs) (p < .01), as well as ovarian fibrosis, in PCOS rats. Additionally, SA treatment impacted the serum levels of sex hormones in PCOS rats. Luteinizing hormone (LH) and testosterone (T) levels were decreased (p < .01, p < .05), and follicle-stimulating hormone (FSH) levels were increased (p < .05). SA administration also decreased triglyceride (TG) (p < .01) and total cholesterol (TC) levels (p < .05) and increased high-density lipoprotein cholesterol (HDL-C) levels (p < .01), thereby alleviating letrozole-induced metabolic dysfunction in PCOS rats. Furthermore, SA treatment targeted insulin resistance (IR) and increased the messenger RNA (mRNA) levels of antioxidant enzymes in the ovaries of PCOS rats. Finally, SA treatment enhanced the activity of peroxisome proliferator-activated receptor-γ (PPAR-γ), reduced the activation of transforming growth factor-ß1 (TGF-ß1)/Smads, and decreased collagen I, α-smooth muscle actin (α-SMA), and connective tissue growth factor (CTGF) levels in the ovaries of PCOS rats. These observations suggest that SA significantly ameliorates metabolic dysfunction and oxidative stress and ultimately reduces ovarian fibrosis in rats with letrozole-induced PCOS.

Mitochondria-associated membranes contribution to exercise-mediated alleviation of hepatic insulin resistance: Contrasting high-intensity interval training with moderate-intensity continuous training in a high-fat diet mouse model.

OBJECTIVE: Mitochondria-associated membranes (MAMs) serve pivotal functions in hepatic insulin resistance (IR). Our aim was to explore the potential role of MAMs in mitigating hepatic IR through exercise and to compare the effects of different intensities of exercise on hepatic MAMs formation in high-fat diet (HFD) mice. METHODS: Male C57BL/6J mice were fed an HFD and randomly assigned to undergo supervised high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT). IR was evaluated using the serum triglyceride/high-density lipoprotein cholesterol ratio (TG/HDL-C), glucose tolerance test (GTT), and insulin tolerance test (ITT). Hepatic steatosis was observed using hematoxylin-eosin (H&E) and oil red O staining. The phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase 3 beta (PI3K-AKT-GSK3ß) signaling pathway was assessed to determine hepatic IR. MAMs were evaluated through immunofluorescence (colocalization of voltage-dependent anion-selective channel 1 [VDAC1] and inositol 1,4,5-triphosphate receptor [IP3R]). RESULTS: After 8 weeks on an HFD, there was notable inhibition of the hepatic PI3K/Akt/GSK3ß signaling pathway, accompanied by a marked reduction in hepatic IP3R-VDAC1 colocalization levels. Both 8-week HIIT and MICT significantly enhanced the hepatic PI3K/Akt/GSK3ß signaling and colocalization levels of IP3R-VDAC1 in HFD mice, with MICT exhibiting a stronger effect on hepatic MAMs formation. Furthermore, the colocalization of hepatic IP3R-VDAC1 positively correlated with the expression levels of phosphorylation of protein kinase B (p-AKT) and phosphorylation of glycogen synthase kinase 3 beta (p-GSK3ß), while displaying a negative correlation with serum triglyceride/high-density lipoprotein cholesterol levels. CONCLUSION: The reduction in hepatic MAMs formation induced by HFD correlates with the development of hepatic IR. Both HIIT and MICT effectively bolster hepatic MAMs formation in HFD mice, with MICT demonstrating superior efficacy. Thus, MAMs might wield a pivotal role in exercise-induced alleviation of hepatic IR.